# NM_003585.5(DOC2B):c.655G>A (p.Glu219Lys)

https://sugi.bio/variant/doc2b-p-glu219lys

## Summary

**DOC2B p.Glu219Lys (c.655G>A)** is classified **Uncertain significance** in DOC2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely pathogenic (0.9691); Very rare (popmax 0.00137%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1555523243 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00137%, afr)

## For patients & families {#patients}

This is a change in the DOC2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DOC2B](https://sugi.bio/atlas/gene/DOC2B/) |
| Protein change (HGVS p.) | p.Glu219Lys |
| Coding change (HGVS c.) | c.655G>A |
| MANE Select transcript | [NM_003585](https://www.ncbi.nlm.nih.gov/nuccore/NM_003585) |
| dbSNP | [rs1555523243](https://www.ncbi.nlm.nih.gov/snp/rs1555523243/) |
| Variant type | single nucleotide variant |
| Location | chr17:161525-161525 (GRCh38) |
| ClinVar | [VCV2392654](https://www.ncbi.nlm.nih.gov/clinvar/variation/2392654/) |

**All HGVS expressions:** `NC_000017.10:g.11316C>T`, `NC_000017.11:g.161525C>T`, `NG_021143.2:g.25106G>A`, `NG_021143.3:g.25125G>A`, `NM_003585.5:c.655G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9691)
- REVEL 0.512 (indeterminate)
- SaProt LLR -15.304 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.658, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.2**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.72 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00137%** (afr) · FAF95 2.9e-05% · FAF99 1.1e-05% · 1/73,162 in the highest group · 4/1,399,386 alleles overall — very rare (popmax 0.00137%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00137% | 73,162 |
| South Asian | 0.00119% | 84,060 |
| European (non-Finnish) | 0.000174% | 573,493 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DOC2B** population constraint: LOEUF 1.371, pLI 1.4579e-06, missense-Z -1.3442. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **219** lies in the c2 1 domain.

AlphaFold model confidence (whole protein): pLDDT 79.21, 61% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-17.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-17 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DOC2B variant pages (same residue, condition, or type): [DOC2B p.Ala103Thr](/variant/doc2b-p-ala103thr), [DOC2B p.Ala295Thr](/variant/doc2b-p-ala295thr), [DOC2B p.Ala54Glu](/variant/doc2b-p-ala54glu), [DOC2B p.Ala58Ser](/variant/doc2b-p-ala58ser), [DOC2B p.Ala63Thr](/variant/doc2b-p-ala63thr), [DOC2B p.Arg186Cys](/variant/doc2b-p-arg186cys), [DOC2B p.Arg186His](/variant/doc2b-p-arg186his), [DOC2B p.Arg209His](/variant/doc2b-p-arg209his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2392654). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*